Title: Patient-Level Meta-analysis: Effects of age of initiation, duration of therapy and intensity of treatment (dosing schedule) with factor VIII prophylaxis on prevention of hemophilic arthropathy using joint scoring via sensitive and specific magnetic resonance imaging (MRI) and sensitive physical joint examination to assess joint outcome. Abstract: This proposal will address the development of structural and functional joint disease in severe hemophilia A along with the benefits of prophylaxis in preventing or ameliorating joint damage. Chronic arthropathy in severe hemophilia is an important morbidity caused by microscopic or large hemorrhages into joints and results in pain that limits employment and social participation. Prophylaxis, or routine infusions of factor VIII to prevent bleeding, is the standard of care therapy to prevent joint and life-threatening bleeding events. However, while high-dose, frequent infusions begun before the age of two years (called primary prophylaxis) is effective in preventing chronic arthropathy, many questions remain regarding whether and to what degree delayed or less intensive prophylaxis prevents, limits or reverses joint damage. In addition, it is unknown whether and to what extent prophylaxis can help teens and adults with established joint disease (secondary prophylaxis). The aim of this proposal is to use existing data from three research studies that include joint imaging with sensitive and specific magnetic resonance imaging (MRI) in order to determine the natural history of hemophilic joint disease, the long-term outcome of primary prophylaxis and the impact of secondary prophylaxis. Two of the three studies include serial measurements over time and all of the studies include patients on prophylaxis in comparison to no prophylaxis. Two of the studies include patients who began prophylaxis by the age of two years, and all three studies include patients who began prophylaxis beyond the age of two years. In this proposal, individual patient data will be aggregated and analyzed as a single study. Analytic models are proposed to determine the time-trajectory of joint damage in patients on no-prophylaxis, and to determine the effects of prophylaxis on preventing, reversing or reducing the degree of joint damage. In addition, the study will address the impact of age of starting prophylaxis, FVIII dose and dose frequency on outcome of prophylaxis. Because the three studies incorporate a large number of subjects (at least 56 patients on no-prophylaxis, 60 patients on primary prophylaxis and 106 patients on secondary prophylaxis, and include four to six joint images for each MRI study, it is likely that the objectives of the proposed study will be met.